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SLC39A4
solute carrier family 39 member 4
SLC39A4 is located on the long (q) arm of chromosome 8, at band 8q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
SLC39A4 belongs to the solute carrier 39 (SLC39) family, also known as the ZIP (Zrt- and Irt-like protein) family of metal transporters. The encoded protein, ZIP4, is expressed primarily on the apical membrane of small intestinal enterocytes, where it mediates the uptake of zinc from digested food into the bloodstream. Zinc serves as a cofactor for hundreds of enzymes and transcription factors, making adequate absorption essential for growth, immune function, wound healing, and neurological development.
Pathogenic variants in SLC39A4 result in acrodermatitis enteropathica, a rare autosomal recessive disorder that typically presents in infancy following weaning from breast milk. Affected individuals develop severe zinc deficiency despite normal dietary intake, manifesting as periorificial and acral dermatitis, alopecia, chronic diarrhoea, and recurrent infections. The condition is readily treatable with lifelong oral zinc supplementation, underscoring the clinical importance of recognising genetic defects in zinc transport.
What the gene does
The SLC39A4-encoded ZIP4 protein functions as a zinc-specific importer, facilitating the movement of zinc ions (Zn²⁺) from the intestinal lumen into enterocytes. ZIP4 is tightly regulated in response to dietary zinc availability: under zinc-deficient conditions, the protein is localised to the apical membrane to maximise absorption, whereas zinc-replete states trigger endocytosis and degradation of ZIP4, preventing toxic accumulation.
At the cellular level, ZIP4 is believed to operate as a divalent cation transporter with high selectivity for zinc, though it may also transport other metals such as iron and manganese under certain conditions. The protein undergoes post-translational modifications, including glycosylation and ubiquitination, which regulate its trafficking and turnover. Loss of functional ZIP4 abolishes the adaptive increase in zinc absorption normally seen during dietary insufficiency, rendering individuals wholly dependent on baseline passive diffusion mechanisms that cannot sustain adequate zinc levels for normal physiology.
Beyond the intestine, SLC39A4 is expressed at lower levels in other tissues, including skin, kidney, and placenta, suggesting roles in zinc homeostasis at multiple sites. The protein's function is critical during periods of high zinc demand, such as infancy, pregnancy, and lactation.
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Chromosome location
SLC39A4 is located on the long arm of chromosome 8 at cytogenetic band 8q24.3. The gene spans approximately 11 kilobases of genomic DNA and comprises 13 exons. This chromosomal region is gene-dense and includes several other metabolic and transporter genes, though SLC39A4 itself is not known to be part of a larger gene cluster with shared regulatory elements.
Protein structure
The SLC39A4 protein is 647 amino acids in length and contains multiple predicted transmembrane domains characteristic of ZIP family transporters, typically modelled as eight membrane-spanning helices. Structural predictions indicate two disordered regions: amino acids 236-255 and amino acids 458-484, which may confer flexibility for conformational changes during zinc translocation or regulatory interactions. A functionally important motif spanning amino acids 452-454 is essential for SLC39A4 endocytosis, mediating the internalisation and degradation of the transporter in response to zinc sufficiency. The cytoplasmic N- and C-terminal domains are thought to contain sites for post-translational modification and adaptor protein binding, coordinating the protein's localisation and stability.
Key variants
Pathogenic variants in SLC39A4 are distributed throughout the coding sequence, with missense, nonsense, frameshift, and splice-site mutations all reported. Most disease-causing variants result in complete loss of ZIP4 function, either through premature termination, protein misfolding, or failure to traffic correctly to the apical membrane. Founder mutations have been identified in specific populations, including individuals of Middle Eastern and Mediterranean ancestry. Genotype-phenotype correlation is limited, as most biallelic loss-of-function variants produce a similar severe phenotype that is fully reversible with zinc therapy.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in SLC39A4 cause acrodermatitis enteropathica, a rare autosomal recessive disorder characterised by impaired intestinal zinc absorption. Clinical features typically emerge in early infancy, particularly after weaning, and include a distinctive triad of periorificial and acral dermatitis, alopecia, and diarrhoea. Without treatment, affected individuals experience failure to thrive, secondary immunodeficiency with increased susceptibility to bacterial and fungal infections, and neuropsychiatric symptoms. The condition is readily diagnosed through low serum zinc and alkaline phosphatase levels, and responds dramatically to oral zinc supplementation, which must be continued lifelong.
UK clinical status
SLC39A4 is listed as a green (high-evidence) gene on multiple NHS Genomic Medicine Service panels, reflecting its established role in Mendelian disease. It appears on the Epidermolysis bullosa and congenital skin fragility panel (R164), the Intestinal failure or congenital diarrhoea panel (R331), the Likely inborn error of metabolism panel (R98), the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), the Rare genetic inflammatory skin disorders panel (R332), and the Undiagnosed metabolic disorders panel. This broad inclusion reflects the multisystem presentation of acrodermatitis enteropathica and the importance of genetic testing in infants with unexplained dermatitis, diarrhoea, or failure to thrive.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for SLC39A4-related conditions?
Acrodermatitis enteropathica follows an autosomal recessive inheritance pattern, meaning an individual must inherit pathogenic variants in both copies of SLC39A4 to develop the condition. Carriers with one variant typically have normal zinc absorption.
Can dietary changes prevent acrodermatitis enteropathica?
No, dietary zinc alone cannot overcome the genetic defect in SLC39A4. Individuals with acrodermatitis enteropathica require pharmacological doses of oral zinc supplementation, typically zinc sulfate or zinc acetate, prescribed and monitored by a healthcare provider.
Is genetic testing for SLC39A4 available on the NHS?
Yes, SLC39A4 sequencing is available through NHS genomic testing for individuals meeting clinical criteria, particularly infants and children presenting with characteristic skin lesions, diarrhoea, and low serum zinc. Testing is typically arranged by specialist metabolic or dermatology services.